EP1827569A4 - Corpus callosum neuromodulation assembly - Google Patents
Corpus callosum neuromodulation assemblyInfo
- Publication number
- EP1827569A4 EP1827569A4 EP05742697A EP05742697A EP1827569A4 EP 1827569 A4 EP1827569 A4 EP 1827569A4 EP 05742697 A EP05742697 A EP 05742697A EP 05742697 A EP05742697 A EP 05742697A EP 1827569 A4 EP1827569 A4 EP 1827569A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- lead body
- corpus callosum
- neuromodulation assembly
- lead
- electrical
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Ceased
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
- A61N1/36103—Neuro-rehabilitation; Repair or reorganisation of neural tissue, e.g. after stroke
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
- A61N1/36067—Movement disorders, e.g. tremor or Parkinson disease
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
- A61N1/36071—Pain
- A61N1/36075—Headache or migraine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/3605—Implantable neurostimulators for stimulating central or peripheral nerve system
- A61N1/3606—Implantable neurostimulators for stimulating central or peripheral nerve system adapted for a particular treatment
- A61N1/36082—Cognitive or psychiatric applications, e.g. dementia or Alzheimer's disease
Definitions
- the present invention is directed to a neuromodulation assembly for stimulating neural tissue.
- Electrical stimulation of neural tissue is becoming an increasingly preferred form of therapy for various neurological conditions and disorders. Such therapy provides distinct advantages over surgical lesioning techniques since electrical stimulation is a reversible and adjustable procedure that provides continuous benefits as the patient's disease progresses and the patient's symptoms evolve.
- electrical stimulation of peripheral nerves and the spinal cord is approved for treatment of neuropathic pain.
- electrical stimulation of the subthalamic nucleus and the globus pallidus interna is approved for treatment of Parkinson's disease and electrical stimulation of the ventral intermediate nucleus is approved for treatment of essential tremor.
- electrical stimulation of the ventral intermediate nucleus is approved for treatment of essential tremor.
- the present invention provides an neuromodulation assembly comprising a lead body having a top surface and a bottom surface.
- the lead body has a curvature that mimics the curvature of the trunk, the genu, the splenium, or the rostrum of the corpus callosum in an operative position of the lead body.
- the neuromodulation assembly further comprises an electrical contact exposed at the bottom surface and not the top surface of the lead body, a conductor coupled to the electrical contact and extending from the lead body, and an anchor disposed on the conductor.
- the present invention provides an neuromodulation assembly comprising a lead body having a top surface and a bottom surface.
- the lead body has a curvature that mimics the curvature of the trunk, the genu, the splenium, or the rostrum of the corpus callosum in an operative position of the lead body.
- the neuromodulation assembly further comprises an electrical contact exposed at the bottom surface and not the top surface of the lead body, a conductor coupled to the electrical contact and extending from the lead body, an accessory strand extending from the lead body, and an anchor disposed on the accessory strand.
- the present invention provides a method of stimulating the corpus callosum comprising placing an electrical lead having an electrode disposed thereon in communication with a corpus callosum and activating the electrode to apply an electrical signal to the corpus callosum to stimulate the corpus callosum.
- the present invention provides a method of securing an electrical lead comprising a lead body having an electrode disposed thereon. The method comprises anchoring the lead to the dura mater of the brain.
- FIG. 1 depicts a sagittal section of the brain showing the corpus callosum.
- FIG. 2 is a perspective view of an embodiment of a neuromodulation assembly according to the present invention.
- FIG. 3 is a bottom view of a neuromodulation assembly according to the present invention.
- FIG. 4 depicts an embodiment of a neuromodulation assembly according to the present invention positioned on the trunk of the corpus callosum.
- FIG. 5 depicts an embodiment of a neuromodulation assembly according to the present invention positioned on the genu of the corpus callosum.
- FIG. 6 depicts an embodiment of a neuromodulation assembly according to the present invention positioned on the rostrum of the corpus callosum.
- FIG. 7 depicts an embodiment of a neuromodulation assembly according to the present invention positioned on the splenium of the corpus callosum.
- FIG. 8 depicts a lead body of the present invention in a pre-operative position.
- FIG. 9 depicts an alternative embodiment of a neuromodulation assembly according to the present invention.
- FIG. 10 depicts a neuromodulation kit according to an embodiment of the present invention.
- FIG. 11 depicts a neuromodulation assembly of the present invention wherein the lead body is in a pre-operative position inside a cannula.
- FIG. 12 depicts the neuromodulation assembly of FIG.
- FIG. 11 wherein the lead body is shown exiting the distal end of the cannula.
- FIG. 13 is a sagittal section of the brain illustrating a cylindrical lead that is positioned within the corpus callosum along the longitudinal axis thereof.
- FIG. 14 is a diagrammatic view of a patient in which an embodiment of a neuromodulation assembly has been implanted.
- FIG. 15 depicts a neuromodulation assembly wherein the lead body is one the bottom surface of the trunk of the corpus callosum.
- the present invention provides embodiments of electrical lead assemblies for neuromodulation of the corpus callosum.
- the corpus callosum 10 is located between the hemispheres in the floor of the interhemispheric fissure and the roof of the lateral ventricles.
- the corpus callosum 10 has two anterior parts, the rostrum 20 and the genu 30, a central part, the trunk 40 (also referred to as the body of the corpus callosum), and a posterior part, the splenium 50.
- the anterior parts 20 and 30 are situated in the midline deep to the upper part of the inferior frontal gyrus. As illustrated in FIG.
- the genu 30 blends below into the rostrum 20, which is thin and tapered. Rostrum 20 is continuous downward in front of the anterior commissure, with the lamina terminalis.
- the curved genu 30 wraps around and forms the anterior wall and adjacent part of the roof of the frontal horn as it extends obliquely forward and lateral to connect the frontal lobes.
- the genu 30 blends posteriorly into the trunk 40, located above the body of the lateral ventricle.
- the genu 30 and the trunk 40 of the corpus callosum 10 form the roof of both the frontal horn and the body of the lateral ventricle.
- the splenium 50 is situated deep to the supramarginal gyrus and the lower third of the pre-and postcentral gyri. As illustrated in FIG. 1, the splenium 50 is the thick rounded posterior end of the corpus callosum 10 and is situated dorsal to the pineal bpdy and the upper part of the medial wall of the atrium.
- the splenium 50 contains a fiber tract, the forceps major, which forms a prominence, called the bulb, in the upper part of the medial wall of the atrium and occipital horn as it extends posteriorly to connect the occipital lobes.
- a neuromodulation assembly 60 comprising a lead body 70 having a top surface 80 and a bottom surface 90.
- the terms “top,” “bottom,” and “under-surface” are defined relative to the operative position of lead body 70 of neuromodulation assembly 60.
- the term “operative position” refers to the position of lead body 70 when lead body 70 is positioned on the target region of the corpus callosum 10 and neuromodulation assembly 60 is ready to be activated to initiate therapy to the target region of the corpus callosum 10.
- the "target region of the corpus callosum” is the trunk, genu, rostrum, or splenium of the corpus callosum.
- an electrical contact 100 from an electrode and preferably a plurality (i.e.
- neuromodulation assembly 60 further comprises a conductor 110 that is coupled to an electrode having an electrical contact 100.
- Conductor 110 extends from lead body 70 to directly or indirectly be connected to an implantable pulse generator.
- conductor 110 of neuromodulation assembly 60 may further comprise a connector 125 to connect to a mating connector of an extension lead, which in turn is connectable to an implantable pulse generator.
- Neuromodulation assembly 60 further comprises an anchor 115, and preferably a plurality of anchors 115, which in the embodiment depicted in FIG.
- lead body 70 is disposed on conductor 110.
- the present invention provides embodiments of lead body 70 that each have a curvature that mimics the curvature of a target region of the corpus callosum 10.
- lead body 70 has a curvature that i mimics the curvature of the trunk 40 of the corpus callosum 10 in an operative position of lead body 70.
- conductor 110 preferably extends from substantially the center of lead body 70.
- lead body 70 has a curvature that mimics the curvature of the genu 30 of the corpus callosum 10 in an operative position of lead body 70. Referring to FIG.
- lead body 70 has a curvature that mimics the curvature of the rostrum 20 of the corpus callosum 10 in an operative position of lead body 70.
- lead body 70 has a curvature that mimics the curvature of the splenium 50 of the corpus callosum 10 in an operative position of lead body 70.
- conductor 110 preferably extends from one of the side ends of lead body 70.
- the trunk 40, the genu 30, the rostrum 20, and the splenium 50 of the corpus callosum 10 are described above and are well-defined neuroanatomical sites.
- the curvatures of these regions are well known to one of ordinary skill in the art. Because the curvatures of lead bodies 70 of these embodiments of the present invention mimic the curvatures of these regions, such curvatures of lead bodies 70 will also be well-understood by one of skill in the art. In general, in embodiments where lead body 70 mimics the curvature of the trunk 40 or the rostrum 20, lead body 70 has a cambered configuration. In embodiments where lead body 70 mimics the curvature of the splenium 50, lead body 70 has a generally J-shaped configuration.
- neuromodulation assembly 60 further comprises an anchor 115 for securing lead body 70 in the brain. As illustrated in FIG. 2, in an embodiment, anchor(s) 115 is disposed on conductor 110.
- neuromodulation assembly 60 comprises an accessory strand 120, or a plurality of accessory strands 120 as specifically illustrated in FIG. 9, which extends from lead body 70 and has an anchor 115 disposed thereon.
- each accessory strand 120 has at least one anchor 115 disposed thereon.
- anchor 115 is preferably slidably disposed on conductor 110 or accessory strand 120 so that anchor 115 can be appropriately moved along the longitudinal axis of conductor 110 or accessory strand 120 to be positioned adjacent the desired anchoring site of the brain.
- Anchor 115 may be any structure known in the art that is suitable for anchoring lead body 70 in the brain.
- Non-limiting examples of anchor 115 include a tine, hook, suture sleeve, or twist-lock as described in U.S. Patent No. 5,843,146, which is incorporated by reference herein.
- electrical contacts 100 of electrodes are exposed at the bottom surface 90 of lead body 70.
- such electrodes are adjustably powerable.
- the pulsing parameters of the electrodes may be adjusted to initiate, stop, increase, or decrease the pole combinations, energy, amplitude, pulse width, waveform shape, frequency, and/or voltage or any other pulsing parameter known to one of skill in the art to adjust the degree of stimulation delivered thereby.
- each electrode is selectively powerable such that the pulsing parameters of an electrode can be adjusted independent of the pulsing parameters of another electrode .
- the selective powerability over each electrode may be achieved by employed a system including a programmer 520 coupled via a conductor 530 to a telemetry antenna 540.
- the programmer 520 is capable of sending signals via the telemetry antenna 540 to control the electrical signal delivered to electrodes.
- Such a system permits the selection of various pulse output options after the neuromodulation assembly 60 is implanted using telemetry communications.
- the present invention also contemplated radio-frequency systems to selectively power the electrodes.
- the independent powerability of the electrodes also provides a practitioner with a means of modify or steering the direction of stimulation as the locus of stimulation can be selectively adjusted to precisely target portions of the target region of the corpus callosum 10 to achieve the desired therapy.
- electrode having electrical contact 100a may be powered to stimulate an area adjacent thereto while the signal to the electrode having electrical contact lOOe may be substantially minimized to reduce or stop stimulation to an area adjacent to electrical contact lOOe.
- the locus of stimulation can be selectively adjusted and/or steered in this embodiment of neuromodulation assembly 60, specific areas of the target regions of the corpus callosum 10 can be precisely targeted to achieve the desired therapy.
- lead body 70 is fabricated from a flexible material that is deformable from a pre-operative position to the operative position and is configured to retain its shape when in the operative position. In a pre-operative position, illustrated in FIG. 8, lead body 70 is folded at an angle sufficient to clear the superficial levels of the brain above the corpus callosum 10, such as the venous complexes and superior sagittal sinus upon entry into the brain.
- lead body 70 can unfold and assume the operative position on the trunk, genu, rostrum, or splenium of the corpus callosum.
- the flexible material of lead body 70 may comprise, for example, a rubber, a shape memory alloy such as nickel-titanium alloys ("Nitinol”) and copper based alloys, or a superelastic material.
- top surface 80 of lead body 70 may comprise a fastener 135 or a plurality of fasteners 135 that cooperates with portions of an installation tool to secure an installation tool to lead body 70.
- Non-limiting examples of suitable fasteners 135 include a strap, buckle, a groove, a through-hole, or a snap.
- any fastening mechanism may be used to secure an installation tool to lead body 70 such as, for example, a hook-and eye mechanism, a hook and loop mechanism such as that employed under the tradename VELCRO, clamps, staples, and any type of male-female mating members such as nuts and screws, rivets, and the like.
- the present invention provides a neuromodulation kit comprising an neuromodulation assembly 60 having a lead body 70 including a pair of fasteners 135 (illustrated in FIG.
- Arms 170a and 170b have distal ends configured to releasably cooperate with fasteners 135 of lead body 70.
- fasteners 135 are grooves that receive the distal ends of arms 170a and 170b, such distal ends being flared to prevent disengagement from fasteners 135.
- other fastening mechanisms well-known to one of skill in the art can be used to secure distal ends of arms 170a and 170b to lead body 70.
- fasteners 135 can comprise male fasteners and the distal ends of arms 170 can have female fasteners 'attached thereto or integral therewith that act in cooperation with the male fasteners of lead body 70 to secure installation tool 130 to lead body 70.
- installation tool 130 may further comprise a second pivot 190 located proximal to first pivot 180 connecting arms 170a and 170b.
- the present invention also provides a corpus callosum neuromodulation system including neuromodulation assembly 60 and further including components useful in identifying, monitoring, or affecting a target region of the corpus callosum 10.
- such a system could include a component for lesioning and temperature monitoring, and/or a component that has a fiberoptic monitor which allows telemetric intracranial monitoring capabilities, and or a microelectrode recording component, and/or a sensing component to incorporate a feedback mechanism to assist in determining whether lead body 70 should be adjusted.
- a sensing component referring to FIG. 14, a sensor 550 can be incorporated with the corpus callosum electrical stimulation system according to the present invention. Sensor 550 can be used with a closed-loop feedback system in order to automatically determine the level of stimulation necessary to provide the desired therapy.
- Sensor 550 may be implanted into a portion of a patient P's body suitable for detecting characteristics, symptoms or attributes of the condition or disorder being treated such as electrical brain activity, cerebral blood flow, and/or vital signs or other chemical and electrical activity of the body.
- Sensors suitable for use in a system according to the present invention include, for example, those disclosed in U.S. Patent No. 5,711,316, which is incorporated by reference herein.
- stimulating electrodes may be intermittently used to record electrical activity.
- one or more electrodes implanted within the brain may serve as a sensor or a recording electrode. When necessary, these sensing or recording electrodes may deliver stimulation therapy to the target region of the corpus callosum.
- the output of an external feedback sensor may communicate with an implanted pulse generator through a telemetry down-link.
- Any sensing functions in accordance with the present invention can be performed locally, distally, or remotely from the target site and the present invention also contemplates use of neuromodulation assembly 60 integration with imaging methods known in the art such as X-rays, computer tomography, magnetic resonance imaging, and functional magnetic resonance imaging.
- imaging methods known in the art such as X-rays, computer tomography, magnetic resonance imaging, and functional magnetic resonance imaging.
- the interhemispheric fissure is dissected using microneurosurgical techniques known to one of skill in the art.
- the interhemispheric fissure is dissected until the corpus callosum is adequately exposed.
- the branches of the anterior communicating artery may be dissected away to create necessary area to implant an neuromodulation assembly 60 of the present invention.
- Neuromodulation assembly 60 is then delivered to the surface of corpus callosum 10 by any appropriate method known in the art. For example, as illustrated in FIG.
- an installation tool may be used which grips and folds lead body 70 into the pre-operative position and then delivers and places lead body 70 in the operative position on the target region of the corpus callosum 10.
- neuromodulation assembly 60 may also be delivered to the corpus callosum 10 via a cannula 200.
- lead body 70 is folded and inserted into cannula 200 and delivered to the corpus callosum 10.
- lead body 70 unfolds and can assume the operative position on the corpus callosum 10.
- cannula 200 may include a guide from which lead body 70 depends, or tracks that direct lead body 70 in an outwardly direction away from cannula 200, when lead body 70 is advanced out of the distal end of cannula 200.
- a guide from which lead body 70 depends, or tracks that direct lead body 70 in an outwardly direction away from cannula 200, when lead body 70 is advanced out of the distal end of cannula 200 are within the knowledge of one of skill in the art and the neuromodulation assembly 60 is not limited to delivery by any particular method.
- lead body 70 can be delivered by any minimally invasive technique such as endoscopically and/or intravascularly. Referring to FIG.
- neuromodulation assembly 60 can be delivered to the target region of the corpus callosum, such as the trunk 40, neuroendoscopically through the lateral ventricle such that lead body 70 is in contact with the under surface 71 of the trunk 40 of the corpus callosum 10.
- neuromodulation assembly 60 is anchored in the brain by securing anchor 115 to the dura mater of the falx and/or the dura mater of the convexity, for example. Closure of the craniotomy can be performed using standard methods well-known to one of skill in the art.
- a tunneling device can then be used to dissect a subcutaneous tunnel down to the subclavicular level, where a subcutaneous pocket can be made to accommodate an implantable pulse generator.
- An extension wire can then be passed through the tunnel to connect the neuromodulation assembly to the pulse generator.
- other sites can be used for implantation of the pulse generator, such as the abdominal wall and the lower back area below the posterior iliac crest.
- the electrodes of lead body 70 may be adjusted post- operatively by turning them on or off, adjusting the voltage, adjusting the frequency, and adjusting other electrical signal parameters through the use of telemetry, RF signals, or other systems known in the art.
- Electromodulation assembly 60 may also be implemented within a drug delivery system to provide chemical stimulation utilizing a drug, pharmaceutical, or therapeutic agent.
- the signal generator is replaced with or includes a pump and the electrodes are replaced with a catheter or drug ports.
- the pump may be implanted below the skin of a patient and has a port into which a hypodermic needle can be inserted through the skin to inject a quantity of a liquid, such as a drug, pharmaceutical, or therapeutic agent.
- a liquid such as a drug, pharmaceutical, or therapeutic agent.
- the liquid agent is delivered from a pump through a catheter port into a catheter.
- the catheter is positioned to deliver the liquid agent to specific infusion sites in the brain.
- 'neuromodulation assembly 60 may be combined with a drug delivery system to provide both chemical and electrical modulation to target regions of the corpus callosum.
- the present invention provides a method of stimulating the corpus callosum 10 by placing an electrode lead having an electrode disposed thereon and preferably a plurality of electrodes, in communication with the corpus callosum 10.
- the method further comprises activating the electrode to apply an electrical signal to the corpus callosum 10 to stimulate the corpus callosum 10.
- the electrical lead can penetrate the thickness 113 of the corpus callosum along the longitudinal axis thereof.
- the electrical lead can be placed on the top surface 113 or the bottom surface 112 of the corpus callosum.
- the electrical lead may be any electrical lead that is configured to stimulate the corpus callosum.
- the electrical lead can be neuromodulation assembly 70 according to the present invention or any other suitable lead, such as a cylindrical lead 210, as illustrated in FIG. 13, which penetrates the corpus callosum 10 along the longitudinal axis thereof.
- cylindrical lead 210 having an electrode 211, and preferably a plurality of electrodes 211, disposed thereon can be inserted in the brain and into the corpus callosum through a cannula guided by a stereotactic apparatus.
- a conductor 212 coupled to electrical contact 211 and extending from lead 210 can be anchored to the skull via a burr hole anchoring device.
- cylindrical lead 210 can be anchored to dura mater, as described above with respect to neuromodulation assembly 60.
- the present invention provides a method of securing in the brain an electrical lead comprising a lead body having an electrode, and preferably a plurality of electrodes, disposed thereon.
- the method comprises anchoring the electrical lead to the dura mater of the brain, such as the dura mater of the convexity or the falx.
- Such an anchoring method may be a preferred method of anchoring an electrical lead in electrical neuromodulation procedures where the lead is positioned on the surface of the target site rather than penetrating the target site.
- such a method may be used to anchor devices that stimulate structures in the brain that are located in cisterns, such as the basal cisterns, or superficial structures, such as the surface of the cerebellum, or the sylvian fissure.
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- Health & Medical Sciences (AREA)
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- Pain & Pain Management (AREA)
- Hospice & Palliative Care (AREA)
- Child & Adolescent Psychology (AREA)
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Abstract
Description
Claims
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
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US56744104P | 2004-05-04 | 2004-05-04 | |
US60841804P | 2004-09-10 | 2004-09-10 | |
US60841704P | 2004-09-10 | 2004-09-10 | |
PCT/US2005/015425 WO2005107854A2 (en) | 2004-05-04 | 2005-05-04 | Corpus callosum neuromodulation assembly |
Publications (2)
Publication Number | Publication Date |
---|---|
EP1827569A2 EP1827569A2 (en) | 2007-09-05 |
EP1827569A4 true EP1827569A4 (en) | 2008-04-16 |
Family
ID=35320746
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP05742697A Ceased EP1827569A4 (en) | 2004-05-04 | 2005-05-04 | Corpus callosum neuromodulation assembly |
EP05745098A Withdrawn EP1804904A2 (en) | 2004-05-04 | 2005-05-04 | Methods of treating neurological conditions by neuromodulation of interhemispheric fibers |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
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EP05745098A Withdrawn EP1804904A2 (en) | 2004-05-04 | 2005-05-04 | Methods of treating neurological conditions by neuromodulation of interhemispheric fibers |
Country Status (3)
Country | Link |
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US (1) | US7697991B2 (en) |
EP (2) | EP1827569A4 (en) |
WO (1) | WO2005107856A2 (en) |
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Also Published As
Publication number | Publication date |
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US20050283201A1 (en) | 2005-12-22 |
WO2005107856A3 (en) | 2007-01-11 |
WO2005107856A2 (en) | 2005-11-17 |
EP1804904A2 (en) | 2007-07-11 |
EP1827569A2 (en) | 2007-09-05 |
WO2005107856A8 (en) | 2006-02-23 |
US7697991B2 (en) | 2010-04-13 |
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